In the therapeutic treatment of cancers (malignant tumors), surgery, radiotherapy, and chemotherapy are appropriately used independently or in combination. Anticancer agents (anti-malignant tumor agents) used for cancer chemotherapy among those therapies mentioned above originally have cytotoxicity, and cause side reactions by damaging not only cancer (malignant tumor) cells but also normal cells.
Examples of the side reactions caused by anticancer agents include blood disorders, digestive organ obstructions, and neuropathy, but the, problem of acute or chronic neuropathy is especially becoming more serious in recent years. It is considered that this is because major side reactions caused by emerging anticancer agents having marked anticancer effect are neuropathies in, many cases, development of neuropathy is enhanced by influence of multi-drug therapies such as the FOLFOX™ therapy, and such side reactions as blood disorders and digestive organ obstructions tend to be improved. Under the current circumstances, in order to control such neuropathy caused by anticancer agents, it is obliged to reduce the doses of anticancer agents or discontinue cancer chemotherapies.
Neuropathies caused by anticancer agents are also observed in sensitive organs such as gustatory organs, as well as in the central nervous system, vegetative nervous system, and peripheral nervous system. Among them, peripheral neuropathies, for example, pains such as intense pain and burning pain, numbness of extremity ends, abnormal sensations such as cold hypersensitivity, dysesthesias such as anesthesia and sensory paralysis, sensory ataxia, muscle force reduction, and the like are highly frequently developed, and cold allodynia and mechanical allodynia especially cause problems as typical symptoms. Examples of anticancer agents that frequently cause such peripheral neuropathies include taxane drugs (paclitaxel, docetaxel), vinca alkaloid drugs (vincristine, vinblastine, vindesine, vinorelbine), and platinum preparations (oxaliplatin, cisplatin).
At present, against peripheral neuropathies caused by anticancer agents, especially allodynia, any effective methods for prophylactic and therapeutic treatments have not been established. Although usefulness of intravenous administration of calcium and magnesium or glutathione have been reported for peripheral neuropathies caused by oxaliplatin, it is hardly used because, for example, such therapy further complicates cancer chemotherapy, and such substances require massive administration. In practical clinical fields, it is undesirably required to control peripheral neuropathies caused by anticancer agents with physiotherapy, complementary therapies such as massage and acupuncture, or combination of drug therapies such as those using steroids, antidepressants, antiepileptics, and opioids, however, effectiveness of these therapies has not been verified, and such therapies themselves frequently cause side reactions (Non-patent documents 1 and 2).
Thrombomodulin has been known as a substance that acts to specifically bind to thrombin so as to inhibit the blood coagulation activity of thrombin, and at the same time, exerts anticoagulant activity so as to significantly promote the ability of thrombin to activate Protein C. Thrombomodulin was first discovered and obtained as a glycoprotein expressed on the vascular endothelial cells of various animal species including humans, and as for the structure thereof, it is composed of 5 regions, namely, an N-terminal region (amino acid residues 1 to 226), a region having six EGF-like structures (amino acid residues 227 to 462), an O-linked glycosylation region (amino acid residues 463 to 497), a transmembrane region (amino acid residues 498 to 521), and a cytoplasmic region (amino acid residues 522 to 557), from the N-terminal side of the protein (Non-patent document 3).
The entire length thrombomodulin is hardly dissolved in the absence of a surfactant, and addition of a surfactant is essential for manufacturing an entire thrombomodulin preparation. A soluble thrombomodulin is also available that can be fully dissolved even in the absence of a surfactant. The soluble thrombomodulin may be prepared by removing at least a part of the transmembrane region or the entire transmembrane region. For example, it has been confirmed that a soluble thrombomodulin consisting of only 3 regions, namely, the N-terminal region, the region having six EGF-like structures, and the O-linked glycosylation region (i.e., a soluble thrombomodulin having an amino acid sequence consisting of amino acid residues 19 to 516 of SEQ ID NO: 9) can be obtained by applying recombination techniques, and that the resulting recombinant soluble thrombomodulin has the same activity as that of the natural thrombomodulin (Patent document 1). Thrombomodulins derived from human urine, and the like are also exemplified (Patent document 2).
As recognized in many cases, as a result of spontaneous mutations or mutations occurring at the time of obtainment, polymorphic mutations have been found in the human genes. At present, thrombomodulin proteins in which the amino acid at the position 473 of human thrombomodulin precursor having the amino acid sequence consisting of 575 amino acid residues is converted to Val or Ala have been identified. In the nucleotide sequence encoding the amino acid sequence, this variation of amino acid residue corresponds to mutation to T or C at the position 1418 (Non-patent document 3). However, the two types of thrombomodulins are completely identical in terms of their activity and physicochemical properties, and it can be considered that they are substantially identical.
As for intended uses of thrombomodulin, the substance has so far been expected for uses in therapeutic and prophylactic treatments of diseases, for example, myocardial infarction, thrombosis (for example, cerebral thrombosis of an acute stage or chronic stage, acute or chronic peripheral thrombosis of artery or vein, and the like), embolism (for example, cerebral embolism of an acute stage or chronic stage, acute or chronic peripheral embolism of artery or vein, and the like), peripheral vessel obstructions (for example, Buerger's disease, Raynaud's disease, and the like), obstructive arteriosclerosis, functional obstructions developed in succession to a cardiac operation, complications of organ transplant, disseminated intravascular coagulation (DIC), angina pectoris, transient ischaemic attack, toxemia of pregnancy, deep venous thrombosis (DVT), and the like. Further, examples of applicable diseases, other than those accompanied by hypercoagulation such as thrombosis and DIC, include liver affections (Patent document 4), absorptive bone diseases (Patent document 5), wound healing (Patent document 6), and the like. Furthermore, as uses of thrombomodulin together with other active ingredients, there have been disclosed wound healing (Patent document 7), protection of brain tissues (Patent document 8), and the like. Moreover, use of thrombomodulin for therapeutic and prophylactic treatments of pain with hematopoietic cell transplantation has been disclosed (Patent document 9).